(1) Technical Field
The present invention relates to a method of treatment in dentistry and orthopedic surgery. More specifically the method provides for improving the seating of an implant in bone and for regenerating a periodontal ligament in the treatment of periodontal disease by administering a combination of cementum attachment protein and cyclosporin A.
(2) Background Art
The roots of teeth are attached to alveolar bone by dense, coronally oriented collagen fibers termed the periodontal ligament (FIG. 1). This ligament is embedded in bone on the one side and anchored to the surface of the tooth root by a specialized connective tissue termed cementum. The periodontal ligament serves two important functions. First it binds teeth to bone in a firm, but not rigid, manner. When forces are applied, suspension of the tooth in the periodontal ligament permits slight movement of the tooth in all directions. Through this mechanism large occlusal forces are transmitted to bone and resolved. Second, the periodontal ligament functions as a barrier restricting access of bacteria to the roots of teeth.
In the absence of such restriction bacteria can penetrate to the connective tissues surrounding the roots of teeth and elicit a destructive inflammatory response. The infection spreads apically between the teeth and gums and destroys the periodontal ligament, cementum and alveolar bone. The first objective in treating periodontal disease is to remove the microbial deposits from the roots of teeth by scaling and root planing. The second objective is to regenerate a fuinctional attachment of teeth to alveolar bone. A key component of such attachment is the periodontal ligament. Despite much effort it has not so far been possible to regenerate a periodontal ligament (Caffesse R G, de la Rosa M, and Mota IF “Regeneration of soft and hard tissue periodontal defects” Am J Dent 15: 339-245, 2002; Needleman I, Tucker R, Gledrys-Leeper E, Worthington H “A systematic review of guided tissue regeneration for periodontal infrabony defects”J Periodont Res 37: 380-388, 2002). Regenerating a periodontal ligament remains as a major objective for treatment of periodontal disease.
Periodontal disease can lead to tooth loss, and the preferred way to replace teeth is by dental implants. Titanium dental implants are having a major impact on dental practice. Technologically, the most remarkable feature is the development of a biologic union (osscointegration) of the titanium implant surface with bone. However, the problem with this union is its complete rigidity, which increases the likelihood of fractures, loosening of attachment screws and other complications. The rigidity of implants also prevents their use in fixed bridges, splints and other prostheses that include natural teeth as abutments. Such problems would be less likely to occur if there were a non-rigid connective tissue sling, like the periodontal ligament naturally occurring around teeth, between the implants and bone surfaces. Inducing the formation of a periodontal ligament around dental implants would improve their function and survival. The presence of cementum is thought to be required for the formation of a periodontal ligament.
To regenerate cementum or any other specialized tissue, it is necessary to attract cells able to produce the constituents of that tissue, secure the attachment of the cells to the intercellular substratum in the desired site, and induce their differentiation into cells secreting tissue-specific constituents. Cell. type-specific chemotactic factors, attachment factors, growth factors and differentiation factors mediate these functions.
Until recently the identity of these factors in cementum was unknown. During the past decade it has been established that the organic matrix of cementum contains attachment proteins not detectable in adjacent structures and a growth factor. Proteins active towards cementum-forming cells (cementoblasts) have been purified and many of their properties defined. A subset of connective tissue cells able to produce cementum has also been characterized. These alkaline-phosphatase-positive cells have properties suggesting that they are connective tissue precursor cells which have commenced differentiation towards the lineage of cementoblasts. Cementoblasts are found alongside blood vessels in the periodontal ligament.
Cementum attachment protein (CAP) is a 57 kilodalton (kDa) collagenous protein which is different from other collagen types and adhesion molecules. The expression of CAP is confined to mineralized tissue-forming cells and precursors originating in the periodontium, so that CAP can be used to identify cells of ccmentoblastic lineage (Liu, HW, Yacobi R, Savion, N, Narayanan AS and Pitaru S. “A New Collagenous Cementum-Derived Attachment Protein is a Marker for Progenitors of the Mineralized Tissues Forming Cell Lineage of the Periodontal Ligament.” J Bone Mineral Res 12:1691-99, 1997). Peridontal cells migrate in response to and attach better to CAP-coated surfaces than do gingival fibroblasts (Pitaru, S. et al. “Specific cementum attachment protein enhances selectively the attachment and migration of periodontal cells to root surfaces.” J. Periodont Res 30:360-68, 1995). We therefore proposed in a previous filing the use of CAP to induce the formation of cementum and a periodontal ligament around dental and orthopedic implants. We have now demonstrated that CAP does, in fact, have this effect, but only under certain conditions.
Turning to another related problem, means of stabilizing of implants used in orthopedic procedures, such as operations to restore joint motion known as arthroplasties, are still being sought. An example is total hip replacement consisting of a stemmed metal replacement for the femoral head articulating with a high-density polyethylene acetabular component, both components fixed to bone by polymethylmethacrylate (PMMA) cement. Similar procedures are used in the knee and other joints. PMMA cement is an insoluble material to fix the components securely in bone and to transfer stresses from the surface of the components to the larger bone surface, thereby reducing the acceptable pressure per unit of the surface. The cement is regarded as the weakest link in the bone-cement-implant composite (Tooms RE, and Harkness JW. “Arthr Introduction and Overview.” In Campbell's Operative Orthopedics, 8th ed, Crenshaw AH, editor, Mosby Year Book, St. Louis, 1992, pp 371-87).
PMMA is technically difficult to use. PMMA is applied as a thick solution. If the polymer is too viscous, it does not easily enter into all the spaces between the implant and bone; if it is too liquid, the strength after polymerization may be inadequate. Even though PMMA is. a cold-curing polymer, the polymerization reaction is exothennic and can generate enough heat to damage tissues locally, as confirmed by histological studies. PMMA is a rigid, brittle solid, which can withstand high compression but fails under tension or shear forces. If there is any movement between the bone and implant surfaces, or if bone is resorbed for any reason, the cement can break. Fragments of PMMA, with a surrounding giant cell response, are often observed. Fragmentation of cement can limit the long-term survival and functional utility of implants, particularly in young and active persons. Allergic reactions to PMA have also been related to limited survival of implants. For these reasons the metal prosthesis is sometimes inserted into bone without PMMA, but such insertions do not always give satisfactory results, and a better procedure is needed.
Another difficult procedure in orthopedics is the attachment or re-attachment of tendons or ligaments to bone. Such a procedure is used in of traumatic ruptures, tendinitis, tendon transfers and other situations. Even before trauma, the direct insertion of a ligament or tendon into bone is a complex structure. At the insertion, collagen fibrils pass directly from the tendon, ligament or joint capsule into the bone cortex. The fibrils may pass through transitional zones of fibrocartilage and mineralized fibrocartilage. Such direct insertions are difficult to repair: a successful surgical procedure may not be accompanied by a return to normal function.
In an attempt to improve healing, collagen implants with additives such as various collagens, fibronectin, platelet derived growth factor (PDGF), bone morphogenetic proteins (BMPs), growth factors, vitamin D or hormones have been proposed in U.S. Pat. No. 5,002,583 to Pitaru, Gan and Noff. A special procedure bonds plastic to the implant. The outer collagen layer is intended to stimulate collagen ingrowth and anchoring. It was believed that these materials would be sufficient to create a biological bond between the surface of the implant and surrounding tissues.
A method for periodontal regeneration was disclosed by Antoniades and Lynch in U.S. Pat. No. 5,124,316. Basically, a growth-promoting amount of a growth factor, such as PDGF, was taught. According to the disclosure, factors inducing differentiation of precursors into cells with cartilage-forming or bone-forming capacity can also be administered. No factors specific formation are disclosed, nor is a method of reattaching ligaments or tendons to bone.
A composition containing an extract of enamel matrix from tooth germs for inducing bonding between mineralized tissue parts was disclosed by Hammarstrom, Blomlof and Lindskog in U.S. Patent No. 5,418,221. The active components in the extract have been defined, but its periodontal regeneration properties are reported to be in the fraction containing the enamel matrix proteins amelogenins, which are different from CAP and CGF (Hammarstrom L, Heijl L, and Gestrelius S. “Periodontal Regeneration in a Buccal Dehiscence Model in Monkeys After Application of Enamel Matrix Proteins.” J Clin Periodontol 24:669-77, 1997). These investigators did not find cell-adhesion activity or growth factor in their preparations (Gestrelius S. Andersson C, Linstrom D, Hammarstrom L and Somerman M. “In vitro Studies on Periodontal Ligament Cells and Enamel Matrix Derivative.” J Clin Pcriodontol 24:685-92, 1997).
A problem with the first two methods is that they are not specific enough to prevent osseointegration and to induce formation of the specialized structures (cementum and a periodontal ligament) required for providing a natural anchor for a dental or orthopedic implant. The dense coronally oriented collagen fibers of the truc periodontal ligament not only anchor implants to bone in a firm, but not rigid, manner, they also limit penetration of bacteria into connective tissues around the implant. Following implantation, loose connective tissues around the implant quite often become infected, resulting in inflammation and marginal bone resorption. A correctly reconstituted periodontal ligament could decrease the risk of this complication.
As for Hammarstrom's enamel extract, when we prepared it, we detected no CAP by biochemical procedures. Moreover, it would be preferable to use a defined, purified protein.
It was published that cyclosporin A (CSA) augments the formation of cementum in the rat (Ayanoglou CM, Lesty C. New cementum formation induced by cyclosporin A: a histological, ultrastructural and histomorphometric study in the rat. J Periodont Res 32: 543-556, 1997). These studies were performed in rats with intact teeth. There is no information on effects of CSA on dental or orthopedic implants, or on synergistic effects with CAP.